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CRISPR interference identifies vulnerable cellular pathways with bactericidal phenotypes in Mycobacterium tuberculosis
Molecular Microbiology ( IF 3.6 ) Pub Date : 2021-08-04 , DOI: 10.1111/mmi.14790
Matthew B McNeil 1, 2 , Laura M Keighley 1 , Josephine R Cook 1 , Chen-Yi Cheung 1 , Gregory M Cook 1, 2
Affiliation  

Mycobacterium tuberculosis remains a leading cause of death for which new drugs are needed. The identification of drug targets has been advanced by high-throughput and targeted genetic deletion strategies. Each though has limitations including the inability to distinguish between levels of vulnerability, lethality, and scalability as a molecular tool. Using mycobacterial CRISPR interference in combination with phenotypic screening, we have overcome these individual issues to investigate essentiality, vulnerability and lethality for 94 target genes from a diverse array of cellular pathways, many of which are potential antibiotic targets. Essential genes involved in cell wall synthesis and central cellular functions were equally vulnerable and often had bactericidal consequences. Conversely, essential genes involved in metabolism, oxidative phosphorylation, or amino acid synthesis were less vulnerable to inhibition and frequently bacteriostatic. In conclusion, this study provides novel insights into mycobacterial genetics and biology that will help to prioritize potential drug targets.

中文翻译:

CRISPR干扰识别结核分枝杆菌中具有杀菌表型的脆弱细胞途径

结核分枝杆菌仍然是需要新药治疗的主要死因。通过高通量和有针对性的基因缺失策略已经推进了药物靶点的识别。每个尽管都有局限性,包括无法区分作为分子工具的脆弱性、致命性和可扩展性级别。使用分枝杆菌 CRISPR 干扰与表型筛选相结合,我们克服了这些个别问题,以研究来自各种细胞途径的 94 个靶基因的重要性、脆弱性和致死性,其中许多是潜在的抗生素靶点。参与细胞壁合成和中枢细胞功能的必需基因同样易受攻击,并且通常具有杀菌作用。相反,参与代谢、氧化磷酸化、或氨基酸合成不太容易受到抑制并且经常抑菌。总之,这项研究为分枝杆菌遗传学和生物学提供了新的见解,这将有助于优先考虑潜在的药物靶点。
更新日期:2021-08-04
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